EP2796442B1 - Composé analogue en termes de structure à la cajanine, son procédé de préparation et son utilisation - Google Patents

Composé analogue en termes de structure à la cajanine, son procédé de préparation et son utilisation Download PDF

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EP2796442B1
EP2796442B1 EP12859858.8A EP12859858A EP2796442B1 EP 2796442 B1 EP2796442 B1 EP 2796442B1 EP 12859858 A EP12859858 A EP 12859858A EP 2796442 B1 EP2796442 B1 EP 2796442B1
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Prior art keywords
methoxy
isopentenyl
compound
hydroxyl
vinyl
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German (de)
English (en)
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EP2796442A4 (fr
EP2796442A1 (fr
Inventor
Zhuorong Li
Xingyue JI
Situ Xue
Guanghui ZHENG
Yuhuan LI
Peizhen Tao
Jiandong Jiang
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Institute of Medicinal Biotechnology of CAMS
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C235/62—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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Definitions

  • the present invention describes herein relates to cajanine structure analogous compounds, and methods fro their preparation. These compounds are suitable against viral and bacterial infections,for neuroprotection, and for the treatment of metabolic diseases (e.g., osteoporosis, hyperlipidemia, hyperglycemia).
  • metabolic diseases e.g., osteoporosis, hyperlipidemia, hyperglycemia.
  • the present invention also relates to pharmaceutical compositions of these compounds.
  • Pigeonpea (Ca j anus cajan L.)is a pigeon pea plants (Leguminosae sp), with a wide range of medicinal value.
  • Main function of pigeonpea seeds is the treatment of liver and kidney edema, blood strangury, hemorrhoids leading to hematockezia, etc.
  • Pigeon pea root has the functions of detoxification, removing dampness, and hemostasis, acesodyne, as well as disinsection, mainl used for the treatment of sore throat, hemorrhoids leading to hematockezia, blood strangury and edema, dysuria and so on.
  • Pigeon pea leaves have the functionof detoxification and detumescence, mainly used for the treatment of pediatric chickenpox, ulcers and so on.
  • Pigeon pea leaves contain large amounts of stilbene-type compounds, such as cajanine, cajanine A, cajanine C (chemical structure shown in Figure 1 ), these compounds have a wide range of pharmacological effects, such as anti-osteoporosis.Stilbene-type extracts, can effectively promote bone cell formation and inhibitbone cell absorption ( Refer to Pharmaceutical Journal, 2007, 42 (4): 386-391 ).
  • stilbene-type extract from pigeon pea leaves is demonstrated to significantly lower abnormally elevated serum levels of TC, TG and LDL-C levels (see CN101204418A, 2008.6.25 .).
  • stilbene-type extract from pigeon pea leaves also has anti-hypoxic ischemic brain damage, it has the protection effect on the stability of brain microvascular membranes and brain cell membranes under cerebral ischemic conditions ( Refer to Traditional Chinese Drug Research & Clinical Pharmacology, 2006, 17 (3): 172-174 ).
  • XING-YUE JI et al "Total synthesis of cajanine and its antiproliferative activity against human hepatoma cells ", XING-YUE JI et al, ACTA PHARMACEUTICA SINICA B,vol. 1, no. 2, 1 August 2011 (2011-08-01), pages 93-99 ) report the total synthesis of cajanine and the antiproliferative activity of the cajanine and its analog against a human hepatoma cell line.American scholars (see David C. Hopp et al. US2002/0058707 A1 )also studied the hypoglycemic effect of structure analogous compounds of cajanine, cajanine A, and C, etc.
  • the present invention expands the diversity of molecular structures of cajanine-type compounds by chemical means, synthesize and optimize the structures of natural products for the first time;
  • This invention proposes methods of synthesizing a large number of novel compounds having a stilbene skeleton structure, and showing the results of screening the pharmacological activities of the cajanine-type derivatives synthesized.
  • the researches revealed the structure-activity relationship of these compounds; and found that these compounds had a wide range of strong anti-viral activity (such as anti-HIV, HCV, influenza and Cox, etc.) for the first time.
  • this invention provides the results of the researches on the functions of the above mentioned compounds in neuroprotection, anti-metabolic diseases (such as osteoporosis, hyperlipidemia, hyperglycemia) etc., thereby laying the foundation for realization of optimizing natural products leading to final achievement of active medicines.
  • anti-metabolic diseases such as osteoporosis, hyperlipidemia, hyperglycemia
  • the present invention also completed the first total synthesis of cajanine C; in the meantime, on the basis of patent 201010256856.7 , another new full synthetic scheme of cajanine was also proposed.
  • the present invention adopts the following technical schemes:
  • Substituted may be, but is not limited to substituted by halogen, alkoxy, hydroxyl, alkyl, amino group and alkylamino group.
  • a “substituted phenyl” may be, but is not limited to a phenyl substituted by halogen, alkoxy, hydroxyl, alkyl, amino and substituted amino groups in various positions of the group.
  • heteroaryl ring may be, but is not limited to a pyridine ring, a thiophene ring, a furan ring, etc.
  • alkyl may be, but is not limited to Straight-chain or branched-chain alkyl or cycloalkyl which contains 1 to 18 carbon atoms, e.g., methyl, ethyl, isopropyl, n -propyl, n -butyl, isobutyl, sec -butyl, tert -butyl, n -pentyl, isopentyl, n -hexyl, isohexyl, etc., or a corresponding cycloalkyl. More preferably it is selected from C1-C6 lower alkyl.
  • Alkoxyl may be, but is not limited to an alkoxy group containing 1 to 18 carbon, such as methoxyl, ethoxyl, isopropoxyl, n-propoxyl, n-butoxyl, isobutoxyl, butoxyl, sec -butoxyl, tert -butoxyl, n -pentyloxy, isopentoxy, n -hexyloxyl, isohexyloxy. More preferably it is selected from C1-C6 lower alkoxy group.
  • An"Acyl group may be, but is not limited to that with a substitution of alkyl containing 1-18 carbons or aryl, such as formyl, acetyl, isopropylcarbonyl, n -propylcarbonyl, allylcarbonyl, a cyclopropylcarbonyl, n -butylcarbonyl, isobutylcarbonyl, sec -butylcarbonyl, tert -butylcarbonyl, n -pentylcarbonyl, isopentylcarbonyl, n -hexylcarbonyl, isohexylcarbonyl, phenylcarbonyl, tolylcarbonyl and the like .
  • alkyl containing 1-18 carbons or aryl such as formyl, acetyl, isopropylcarbonyl, n -propylcarbonyl, allylcarbonyl, a cyclopropylcarbony
  • An"alkoxycarbonyl “or "ester group” may be, but is not limited to substitution of analkyl having 1-18 carbons on to an acyloxy (or unsubstituted acylox, i.e. formylox) or an aryloxy group, e.g., formyloxy, acetoxy, isopropionyloxy, n -propionyloxy, acryloyloxy, cyclopropylcarbonylox, n -butylcarbonylox, isobutylcarbonylox, sec -butylcarbonylox, tert -butylcarbonylox, n -pentylcarbonylox, isopentylcarbonylox, n -hexylcarbonylox, isohexylcarbonylox, benzoyloxy, toluoylox, etc.
  • Aminoacyl or “carbamoyl” may be acarbamoyl whose amino group is substituted by1 or 2 alkyls having 1 to 18 carbons, or an arylcarbamoyl amino group whose amino group is substituted by the abovementioned alkyl, e.g., N -methylcarbamoyl, N -ethylcarbamoyl, N -isopropylcarbamoyl, N - n -propylcarbamoyl, N -allylcarbamoyl, N -cyclopropylcarbamoyl, N - n -butylcarbamoyl, N - sec -butylcarbamoyl, N - tert -butylcarbamoyl, N - n -pentylcarbamoyl, N -isopentylcarbamoyl, N -
  • Halo or halogen may be fluoro, chloro, bromo or iodo.
  • the present invention also provides a method for the synthesis of cajanine structure analogous compounds, as shown in the general formulas I, IV, as follows.
  • the present invention provides a method of synthesizing the compound represented by the general formula I:
  • the compounds are synthesized according to Scheme 1: wherein
  • the present invention also provides a method to synthesize a compound having formula IV structure, as described in Scheme 20:
  • the solvent used may be, but is not limited to one of the aprotic polar solvents such as ethanol, acetic acid, methanol and the like, the reaction temperature is between 0 to 100°C; in the preparation of Compound 40, the conditions are consistent with those used in the alkylation step in Scheme 5; in the preparation of Compound 41,
  • the halogenating agent may be, but is not limited to the mixture of N -bromosuccinimide (NBS)and dibenzoyl peroxide (BPO)or liquid bromine, or a mixture of sulfuryl chloride and BPO, or a mixture of sulfuryl chloride and azobisisobutyronitrile (AIBN), a mixture of N -chlorosuccinimide (NCS)and BPO or AIBN, etc.
  • the solvent used may be, but is not limited to one of the non polar solvents such as petroleum ether, carbon tetrachloride, etc., or one of the aprotic polar solvents such as
  • the present invention synthesized of a large number of novel cajanine analogues, completed the total chemical synthesis of cajanine C for the first time, also proposed another total new cajanine synthetic scheme.
  • the present invention also measured for the first time the antiviral, neuroprotective, anti-metabolic diseases (such as osteoporosis, hyperlipidemia, hyperglycemia) as well as other pharmacological activities of cajanine derivatives and cajanine, cajanine A, cajanine C etc, synthesized.
  • the activities of a part of the compounds tested exceed those of the lead compound cajanine.
  • Table 1 The structures and the results of the measurements on the pharmacological activities of the compounds proposed in this invention are shown in Table 1, Table 2, respectively.
  • the compounds of the present invention can be used for inhibiting HIV, HCV viruses, the results are shown in Table 2, wherein the compound 1, 1i, 1j, 1l, 1x, 1y, 1z, 1a', 1b', 8j, 8v, 8w, 10h, 10i, 10j, 101, 10m and so on showed stronger anti-HIV, HCV viral activities. Table2. The activities of the said compounds in inhibiting HIV, HCV viruses in vitro No.
  • the compounds of the present invention are also suitable in neural protection (effects on PC12 cell injury), this invention measured the protective effect of said compounds on PC12 cells from serum-deprived injury, as well as rotenone injury (results shown in Table 3).
  • Compounds proposed in this invention showed significantprotective effect on serum-deprived injury to PC12 cells and rotenone injury to PC12 cells, wherein the compound 1p, 1w, 1z, 8m, 8p, 8w, 10j, 10k, 10l, 10m, 10p, , etc. showed the strongest activities.
  • Table 3 Neuroprotective effect of the said compounds No.
  • the present invention also considers the anti-osteoporotic effect of said compounds.
  • pigeonpea stilbene-type compounds belong to phytoestrogens, the anti-osteoporosis effect of natural products has to do with their estrogen-like effects.
  • This invention studied and confirmed the protective effect of pure cajanine obtained by chemical means on bone osteoporosis in ovariectomized rats, the results showed a stronger in vivo anti-osteoporotic effect than clinical drug raloxifene.
  • the anti-tumor, hypoglycemic, hypolipidemic, anti-inflammatory and analgesic effects of pigeon pea stilbene-type extracts and cajanine, cajanine A, cajanine C have been widely studied and reported.
  • the compounds proposed in this invention are structural analogs of natural lead compounds cajanine, cajanine A and cajanine C, it is a matter of course that the compounds proposed in the present invention possess similar antitumor, hypoglycemic, hypolipidemic, anti-inflammatory and analgesic effects. Accordingly, the present invention also considers the anti-tumor, hypoglycemic, hypolipidemic, anti-inflammatory and analgesic effects of said compounds in medicinal nractice.
  • the weight content of said compound having one of the general formula I, IV or their pharmaceutically acceptable salt in the pharmaceutical composition is in the range of 0.1% to 99.5 %.
  • the pharmaceutical composition contains a weight ratio of 0.5% to 99.5 % of the active ingredient.
  • the present invention provides the application of a pharmaceutical composition in the preparation of medicaments for bacterial and viral infection treatment, neuroprotection, treatment of metabolic diseases (such osteoporosis, hyperlipidemia, hyperglycemia).
  • Figure 1 showed the chemical structures of compounds in pigeon pea stilbene extract.
  • Dissolve compound 5 (10g, 0.0289mol)in 100ml tetrahydrofuran, add into the solution NaH (1.09g, 0.0318mol) and benzaldehyde (3.68g, 0.0347mol), heat to reflux for2h, stop the reaction, pour the mixture into 200ml water, extract with ethyl acetate (3 ⁇ 100ml), pool the organic layers, wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate. Filter the solution and remove the solvent by rotary evaporation, recrystallize the residual oil with petroleum ether/ethyl acetate to obtain 6.2g colorless crystals(72%).
  • Dissolve compound 6 (6g, 0.0201mol) in 50ml dichloromethane, add drop wise BBr 3 solution in methylene chloride (24ml, 1M) at 0°C, react at room temperature for 1h. Wash the reaction solution with water, dry over anhydrous magnesium sulfate. Filter the solution and remove the solvent by rotary evaporation, dissolve the residue with petroleum ether/diethyl ether and feed the solution to a silica gel column, evaporate the soventin eluent to obtain 5.4g white solid (95%).
  • MDCK cells Inoculate MDCK cells into 96-well culture plates and culture in the atmosphere of 5% CO 2 , at 37°C for 24 h.
  • influenza virus A/H1N1, A/H3N2 or B/13/79 type
  • Model groups includes rotenone group and serum-deprived group, add rotenone to the corresponding modules with a final concentration of 4 ⁇ M rotenone to take effect on the cells for 48h, add serum-deprived groups with serum-free DMEM medium to take effect on the cells for 48h.
  • Dosing groups also includes two groups, one using rotenone module as model, another using serum-deprived module as model, and both add in 10 ⁇ M test compounds during modeling. 48h later, add 10 ⁇ l 5mg/ml MTT, subsequently discard the supernatant 4h later and add in 150 ⁇ l DMSO, measure 570nm absorbance to represent the numbers of surviving cells.
  • Infect MT-4 cells with 100TCID50 HIV-1 III B virus at 37°C. 1.5h after adsorption and infection, wash the cells twice with culture medium, prepare cell suspensions with concentrations of 2 ⁇ 10 5 cells ⁇ mL -1 , inoculate 100 ⁇ L of the suspensions into 96-well cell culture plate, add 3-fold dilutions of different concentrations of the drugs, or 4-fold dilutions of a solution of positive drug AZT into each well, duplicate each one of the samples, meanwhile seta cell control group.

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Claims (9)

  1. Groupe de composés ayant les structures présentées dans les formules générales I ou IV :
    Figure imgb0070
    où R1 représente un atome H, un groupe aryle substitué ou non substitué, un groupe hétéro aryle substitué ou non substitué, un groupe alkyle substitué ou non substitué, un résidu aryle substitué ou non substitué, un groupe alcoxy carbonyle ou carboxyle substitué ou non substitué ;
    R2 représente un atome H, un groupe aryle substitué ou non substitué, un groupe hétéro aryle substitué ou non substitué, un groupe alkyle substitué ou non substitué, un résidu aryle substitué ou non substitué, un groupe alcoxy carbonyle ou carboxyle substitué ou non substitué ;
    R3 représente un atome H, un groupe carboxyle, un groupe alcoxy formyle substitué ou non substitué, un groupe carbamoyle substitué ou non substitué, un groupe formyle substitué ou non substitué ;
    R4 représente un atome H, un groupe hydroxyle, un groupe alcoxyle substitué ou non substitué, un groupe formyloxy substitué ou non substitué, un groupe amine substitué ou non substitué ou un atome d'halogène, ou un groupe iso-uréido ;
    R5 représente un atome H, un groupe alkyle saturé ou insaturé, un groupe aryle substitué ou non substitué, un groupe alkyle substitué avec un cycle aryle ;
    R6 représente un atome H, un groupe hydroxyle, un groupe alcoxyle substitué ou non substitué, un groupe amine substitué ou non substitué, un atome d'halogène, un groupe mercapto ou un groupe alkylthio ;
    R7 représente un atome H, un groupe isopentényle, un groupe isopentyle, un groupe 3',7'-diméthyl octadièn-2',6'-yle, un groupe aryle substitué ou non substitué, un groupe allyle, un atome d'halogène, un groupe amine substitué ou non substitué ;
    R8 et R9 peuvent être identiques ou différents, ils peuvent représenter un atome H, un groupe alkyle contenant de 1 à 18 atomes de carbone, respectivement ; le composé est l'un des composés suivants :
    le méthyl 2,4-diméthoxy-6-[(E)-styryl]benzoate ;
    le méthyl 2-hydroxyl-4-méthoxy-6-[(E)-styryl]benzoate ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-butèn-1-yl]benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-butèn-1-yl] benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-phényl propèn-1-yl]benzoate l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-phényl propèn-1-yl]benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-thién-2-yl vinyl]benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-thién-2-yl)vinyl]benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-3-phényl propèn-1-yl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-3-phényl propèn-1-yl]benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-4-phényl butèn-1-yl]benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-4-phényl butèn-1-yl]benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(1E,3E)-phényl butadièn-1,3-yl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(1E,3E)phényl butadièn-1,3-yl] benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-cyclohexyl vinyl]benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-cyclohexyl vinyl]benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(pyrid-4-yl)vinyl]benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(pyrid-4-yl)vinyl]benzoïque ;
    le 2-isopentényl-3-méthoxy-5-[(E)-butèn-1-yl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-phényl propèn-1-yl]phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(thièn-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-3-phényl propèn-1-yl]phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-4-phényl butèn-1-yl]phénol ;
    le 2-isopentényl-3-méthoxy-5-[(1E,3E)-phényl butadièn-1,3-yl]phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-cyclohexyl vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-(pyrid-4-yl) vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-styryl] phénol ;
    le méthyl 2-hydroxyl-4-méthoxy-5-isopentényl-6-[(E)-styryl] benzoate ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(pyrid-2-yl) vinyl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(pyrid-2-yl) vinyl] benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(4-méthoxy pyrid-2-yl)vinyl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(4-méthoxy pyrid-2-yl)vinyl] benzoïque ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(hydroxy pyrid-2-yl)vinyl] benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(3-méthoxy pyrid-2-yl)vinyl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(3-méthoxy pyrid-2-yl)vinyl] benzoïque ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(3-hydroxyl pyrid-2-yl)vinyl] benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(4,6-diméthoxy pyrid-2-yl) vinyl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(4,6-diméthoxy pyrid-2-yl) vinyl] benzoïque ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(4,6-diméthoxy pyrid-2-yl) vinyl] benzoïque ;
    le méthyl 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(6-méthoxy pyrid-2-yl)vinyl] benzoate ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(6-méthoxy pyrid-2-yl)vinyl] benzoïque ;
    l'acide 2-hydroxyl-3-isopentényl-4-méthoxy-6-[(E)-2-(6-hydroxy pyrid-2-yl)vinyl] benzoïque ;
    le méthyl 2-hydroxyl-3-allyl-4-méthoxy-6-[(E)-styryl] benzoate ;
    l'acide 2-hydroxyl-3-allyl-4-méthoxy-6-[(E)-styryl] benzoïque ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(4-méthoxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(4-hydroxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(3-méthoxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(3-hydroxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(2,4-diméthoxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(2,4-dihydroxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(2-méthoxy pyrid-2-yl)vinyl] phénol ;
    le 2-isopentényl-3-méthoxy-5-[(E)-2-(2-hydroxy pyrid-2-yl)vinyl] phénol ;
    le 2-allyl-3-méthoxy-5-[(E)-styryl] phénol ;
    le 1,3-diméthoxy-5-[(E)-3-phényl propèn-1-yl]benzène ;
    le 1,3-dihydroxy-5-[(E)-3-phényl propèn-1-yl]benzène ;
    le 1,3-diméthoxy-5-[(E)-3-acétoxy-4-méthoxy styryl] benzène ;
    le 1,3-diméthoxy-5-[(E)-2-(3,5-diacétoxy phényl propèn-1-yl] benzène ;
    le 1,3-diméthoxy-5-[(E)-2-(3,5-dihydroxy phényl propèn-1-yl] benzène ;
    le 1,3-dihydroxy-5-[(E)-2-(3,5-dihydroxy phényl propèn-1-yl] benzène ;
    le 1,3-diméthoxy-5-[(E)-3,4,5-tri acétoxy styryl] benzène ;
    le 1,3-diméthoxy-5-[(E)-3,4,5-tri hydroxy styryl] benzène.
  2. Procédé destiné à préparer un composé spécifique représentatif des composés I selon la revendication 1, et les composés sont synthétisés selon le schéma 1 :
    Figure imgb0071
     où
    - un ester acéto acétique et une diéthénone sont condensés dans des conditions basiques pour produire le composé 2 ;
    - le composé 2 est alkylé dans des conditions basiques dans un solvant polaire pour produire le composé 3 ;
    - le composé 3 forme le composé 4 par une halogénation de radical libre dans un solvant non polaire ; où
    - le composé 4 se condense avec un triester phosphite pour donner le composé 5 ;
    - le composé 5 réagit avec une cétone ou un aldéhyde pour obtenir le composé 6 ;
    - le composé 6 réagit pour donner le composé 7 par une dé-alkylation en présence d'un agent de dé-alkylation ;
    - le composé 7 se condense avec un hydrocarbure halogéné pour produire le composé 8 et un composé 8' oxy-alkylé, où le composé 8' est un composé conforme à la formule I dont R4 est un groupe méthoxy, R5 est de l'hydrogène, les groupes restants sont tels que définis dans la revendication 1 ; et où
    - un composé selon la formule I est produit par hydrolyse du composé 8, où R8 est un groupe méthyle, R9, R10 sont un hydrocarbure alkyle avec 1 à 18 atomes de carbone substitué ou non substitué, R1, R2, R5 sont identiques à ceux définis en revendication 1.
  3. Procédé destiné à préparer un composé spécifique représentatif des composés I selon la revendication 1, où le composé selon la formule I est synthétisé selon le schéma 2 :
    Figure imgb0072
     où
    - en présence d'un réactif de condensation, un composé selon la formule I tel que décrit dans le schéma 2 se condense avec un des composés variés R9'XH, où X est un atome O, pour produire le composé 9, ou où
    - un composé selon la formule I réagit avec un agent d'acylation pour obtenir un chlorure d'acyle qui, en présence d'un agent de liaison acide, se condense avec des composés R9'XH variés pour produire le composé 9, où
    - R1, R2, R4, R5, R6, R7 sont identiques à ceux définis précédemment dans la revendication 1, R9' est un groupe méthyle.
  4. Procédé destiné à préparer un composé spécifique représentatif des composés IV selon la revendication 1, décrit dans le schéma 20 :
    Figure imgb0073
     Schéma 20 : dans des conditions basiques, le composé 38 est obtenu par une condensation entre un ester acéto acétate et un ester d'acide crotonique, il est ensuite arylisé par une bromination du composé 38 pour obtenir le composé 39, il est alors alkylé pour produire le composé 40, et dans une nouvelle halogénation radicalaire avec un réactif d'halogénation pour obtenir le composé 41, il est condensé avec un réactif phosphine organique pour obtenir le composé 42, à partir de ce dernier, le produit 42 alkylé est obtenu par une réaction de couplage, le produit 42 est ensuite hydrogéné pour produire le composé 43, il est encore hydrogéné pour obtenir le produit 44, ce dernier étant ensuite condensé avec du benzaldéhyde dans des conditions basiques pour obtenir le composé 45, par une dé-alkylation du composé 45, le composé 46 est obtenu, il est ensuite hydrolysé pour obtenir le composé 47.
  5. Utilisation de composés de type stilbène avec un composé représentatif spécifique des composés I et IV selon la revendication 1, ou de sels pharmaceutiquement acceptables de ceux-ci, dans la préparation de médicaments utilisés pour des infections bactériennes et virales, la protection neurale ainsi que pour des maladies métaboliques, lesdites maladies métaboliques comprenant l'ostéoporose, l'hyperlipidémie et l'hyperglycémie.
  6. Composition pharmaceutique pour des infections bactériennes ou virales, la protection neurale et les maladies métaboliques, les compositions pharmaceutiques comprenant une quantité efficace d'un point de vue thérapeutique de composés représentatifs des composés I ou IV tels que listés en revendication 1, ou les sels desdits composés de ceux-ci, et contenant un ou plusieurs adjuvants pharmaceutiquement acceptables, lesdites maladies métaboliques incluant l'ostéoporose, l'hyperlipidémie et l'hyperglycémie.
  7. Composition pharmaceutique selon la revendication 6, dans laquelle lesdits composés représentatifs spécifiques des composés I ou IV tels que listés en revendication 1, ou les sels desdits composés de ceux-ci, fonctionnent comme des ingrédients actifs dont les teneurs pondérales dans les compositions pharmaceutiques sont dans la plage de 0,1 % à 99,5 %.
  8. Composition pharmaceutique selon la revendication 7, où lesdites compositions pharmaceutiques contiennent des ingrédients actifs dans un rapport pondéral de 0,5 % à 99,5 %.
  9. Utilisation de la composition pharmaceutique selon la revendication 6 pour préparer les médicaments pour des infections bactériennes, virales, la protection neurale ou des maladies métaboliques, où lesdites maladies métaboliques incluent l'ostéoporose, l'hyperlipidémie et l'hyperglycémie.
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US20140371232A1 (en) 2014-12-18
CN105030750B (zh) 2018-08-28
JP6203746B2 (ja) 2017-09-27
CN105030750A (zh) 2015-11-11
CN103172512B (zh) 2016-08-03
EP2796442A4 (fr) 2015-11-11
JP2015507618A (ja) 2015-03-12
US9359298B2 (en) 2016-06-07
WO2013091282A1 (fr) 2013-06-27
EP2796442A1 (fr) 2014-10-29

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